Pharmacological Effects of Berberine Hydrochloride Thermosensitive Gel Combined with Paclitaxel on Breast Cancer-Bearing Mice
TANG Lan1, SHEN Miao1, GAO Yan1, TU Chao-jie1, CAO Li-Peng1, SHAN Wei-guang1, FU Lu-lu1*, ZHANG Zhen-hai2*
1. School of Pharmacy, Zhejiang University of Technology, Hangzhou 310014, China; 2. Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Labratory of Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China
Abstract:OBJECTIVE To prepare berberine hydrochloride thermosensitive gelfor intratumoral injection by PLGA-PEG-PLGA and berberine, and investigate the pharmacological effects of combination with paclitaxel injectionafter intratumoral injection on 4T1 tumor bearing mice. METHODS Berberine hydrochloride thermosensitive gel was prepared with PLGA-PEG-PLGA as gel matrix and berberine hydrochloride. Phase transition temperature was selected as the investigation factor to optimize the prescription, and the release results in vitro were investigated by membrane-free dissolution combined with UV method. The 4T1 tumor-bearing Balb/c mouse model was established to evaluate the anti-tumor effect of berberine hydrochloride thermosensitive gel in vivo. RESULTS Berberine hydrochloride thermosensitive gel was successfully prepared. The drug loading was 3 mg·mL-1 and the phase transition temperature of thermosensitive gel was (36.5±0.3)℃, which met the needs of intratumoral injection. The results of in vitro release show that the gel has sustained release effect and can be released for at least 14 days. The results of pharmacodynamic experiments showed that berberine hydrochloride thermosensitive gel combined with paclitaxel injection had better antitumor effect than paclitaxel injection alone (P<0.05). CONCLUSION A thermosensitive gel is successfully prepared in this experiment. The combination of intratumoral injection and paclitaxel injection can enhance the tumor inhibitory effect of paclitaxel on 4T1 tumor-bearing mice, which has a good application prospect.
WANG Y, LIU Y, DU X, et al. The Anti-Cancer Mechanisms of Berberine: A Review[J]. Cancer Manag Res, 2020, 12:695-702.
[2]
YAO M, FAN X, YUAN B, et al. Berberine inhibits NLRP3 Inflammasome pathway in human triple-negative breast cancer MDA-MB-231 cell[J]. BMC Complement Altern Med, 2019, 19(1): 216.
[3]
GU S, SONG X, XIE R, et al. Berberine inhibits cancer cells growth by suppressing fatty acid synthesis and biogenesis of extracellular vesicles [J]. Life Sci, 2020, 257: 118-122.
[4]
PAN Y, ZHANG F, ZHAO Y, et al. Berberine Enhances Chemosensitivity and Induces Apoptosis Through Dose-orchestrated AMPK Signaling in Breast Cancer [J]. J Cancer, 2017, 8(9): 1679-1689.
[5]
KHAN I, JOSHI G, NAKHATE K T, et al. Nano-Co-Delivery of Berberine and Anticancer Drug Using PLGA Nanoparticles: Exploration of Better Anticancer Activity and In Vivo Kinetics [J]. Pharm Res, 2019, 36(10): 149.
[6]
DU X, KHAN A R, FU M, et al. Current development in the formulations of non-injection administration of paclitaxel [J]. Int J Pharm, 2018, 542(1-2): 242-252.
[7]
ABU SAMAAN T M, SAMEC M, LISKOVA A, et al. Paclitaxel's Mechanistic and Clinical Effects on Breast Cancer [J]. Biomolecules, 2019, 9(12):789.
[8]
CHENG Y, JI Y. Mitochondria-targeting nanomedicine self-assembled from GSH-responsive paclitaxel-ss-berberine conjugate for synergetic cancer treatment with enhanced cytotoxicity [J]. J Controlled Release, 2020, 318: 38-49.
[9]
WANG X, WANG Q, LIU Z, et al. Preparation, pharmacokinetics and tumour-suppressive activity of berberine liposomes [J]. J Pharm Pharmacol, 2017, 69(6): 625-632.
[10]
DENG J, WU Z, ZHAO Z, et al. Berberine-Loaded Nanostructured Lipid Carriers Enhance the Treatment of Ulcerative Colitis [J]. Int J Nanomed, 2020, 15: 3937-3951.
[11]
WANG P, CHU W, ZHUO X, et al. Modified PLGA-PEG-PLGA thermosensitive hydrogels with suitable thermosensitivity and properties for use in a drug delivery system [J]. J Mater Chem B, 2017, 5(8): 1551-1565.
[12]
CAO D, ZHANG X, AKABAR M D, et al. Liposomal doxorubicin loaded PLGA-PEG-PLGA based thermogel for sustained local drug delivery for the treatment of breast cancer [J]. Artif Cells Nanomed Biotechnol, 2019, 47(1): 181-191.
[13]
KITAGAWA M, MAEDA T, HOTTA A. PEG-based nanocomposite hydrogel: Thermo-responsive sol-gel transition and degradation behavior controlled by the LA/GA ratio of PLGA-PEG-PLGA [J]. Polym Degrad Stab, 2018, 147: 222-228.
[14]
SHEN J, DENG A, LIU H, et al. Formula Screening and in vitro Drug Release of Tegafur Thermo-sensitive Gel for Intratumor Injection [J]. Chin Pharm(中国药师), 2016, 19(9): 1656-1659.
[15]
MAJIDZADEH H, ARAJ-KHODAEI M, GHAFFARI M, et al. Nano-based delivery systems for berberine: A modern anti-cancer herbal medicine [J]. Colloids Surf B Biointerfaces, 2020, 194: 111188.
[16]
CHENG D, YU N, XU Y-F, et al. Preparation of Paclitaxel Palmitate Liposomes and Preliminary Investigation of Its Pharmacodynamics and Safety [J]. Chin Pharm J(中国药学杂志), 2018, 53(8): 614-619.
[17]
MITTAL S, BROWN N J, HOLEN I. The breast tumor microenvironment: role in cancer development, progression and response to therapy [J]. Expert Rev Mol Diagn, 2018, 18(3): 227-243.